PTRF/Cavin-1 as a Novel RNA-Binding Protein Expedites the NF-κB/PD-L1 Axis by Stabilizing lncRNA NEAT1, Contributing to Tumorigenesis and Immune Evasion in Glioblastoma

Front Immunol. 2022 Jan 6;12:802795. doi: 10.3389/fimmu.2021.802795. eCollection 2021.

Abstract

Background: Immunotherapy, especially checkpoint inhibitors targeting PD-1 or PD-L1, has revolutionized cancer therapy. However, PD-1/PD-L1 inhibitors have not been investigated thoroughly in glioblastoma (GBM). Studies have shown that polymerase 1 and transcript release factor (PTRF/Cavin-1) has an immune-suppressive function in GBM. Thus, the relationship between PTRF and PD-L1 and their role in immune suppression requires further investigation in GBM.

Methods: We used public databases and bioinformatics analysis to investigate the relationship between PTRF and PD-L1. We next confirmed the predicted relationship between PTRF and PD-L1 in primary GBM cell lines by using different experimental approaches. RIP-Seq, RIP, ChIP, and qRT-PCR were conducted to explore the molecular mechanism of PTRF in immunosuppression.

Results: We found that PTRF stabilizes lncRNA NEAT1 to induce NF-κB and PD-L1 and promotes immune evasion in GBM. PTRF was found to correlate with immunosuppression in the public GBM databases. PTRF increased the level of PD-L1 in primary cell lines from GBM patients. We carried out RIP-Seq of GBM cells and found that PTRF interacts with lncRNA NEAT1 and stabilizes its mRNA. PTRF also promoted the activity of NF-κB by suppressing UBXN1 expression via NEAT1 and enhanced the transcription of PD-L1 through NF-κB activation. Finally, PTRF promoted immune evasion in GBM cells by regulating PD-1 binding and PD-L1 mediated T cell cytotoxicity.

Conclusions: In summary, our study identified the PTRF-NEAT1-PD-L1 axis as a novel immune therapeutic target in GBM.

Keywords: PDL1; PTRF; glioblastoma; immunosuppression; lncRNA NEAT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • B7-H1 Antigen / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / etiology*
  • Glioblastoma / metabolism*
  • Glioblastoma / mortality
  • Glioblastoma / pathology
  • Heterografts
  • Humans
  • Kaplan-Meier Estimate
  • Mice
  • NF-kappa B / metabolism*
  • Prognosis
  • RNA Stability
  • RNA, Long Noncoding / genetics*
  • RNA-Binding Proteins / metabolism*
  • Signal Transduction*
  • Tumor Escape

Substances

  • Adaptor Proteins, Signal Transducing
  • B7-H1 Antigen
  • CAVIN1 protein, human
  • CD274 protein, human
  • NEAT1 long non-coding RNA, human
  • NF-kappa B
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • UBXN1 protein, human